Researchers Create Novel Antibiotics Against MRSA

Investigators recently created an experimental antibiotic that has shown the ability to kill methicillin-resistant Staphylococcus aureus (MRSA), which causes deadly antibiotic-resistant infections.

The researchers were able to create this antibiotic because they discovered a flaw in the bacteria that could be exploited in a way that was difficult to counter, according to a study published in Cell Chemical Biology.

The first-line treatment for MRSA is typically trimethoprim-sulfamethoxazole, but MRSA has been developing resistance to this antibiotic. Approximately 30% of infections in sub-Saharan African do not respond to the drug, and the resistance is also spreading in Europe and Asia, the researchers said.

Scientists at the University of Connecticut’s School of Pharmacy have been working to develop an antibiotic that will be difficult for MRSA to develop a resistance against. Once they had multiple drug candidates, the researchers began collecting MRSA strains that were resistant to trimethoprim-sulfamethoxazole.

“Although resistance [to trimethoprim-sulfamethoxazole] in the community is generally less than 10 percent in our local area, resistance elsewhere is climbing,” said researcher Michael Nailor, PharmD. “Additionally, many vulnerable patient populations cannot take trimethoprim-sulfamethoxazole or other generic drugs because of side effects they may cause, and new agents are needed.”

Of the 9 strains collected, 6 had trimethoprim-resistant genes that had not been previously seen in the United States, according to the study. These strains were also resistant to multiple other types of antibiotics.

However, despite resistance to numerous antibiotics, the strains were not resistant to the drug candidates created by the investigators.

“We’ve actually taken strains [of MRSA] from the clinic and shown that our compounds work,” said researcher Stephanie Reeve, PhD student at the University. “We were really happy about these results.”

They found that the drugs were able to kill MRSA without the bacteria developing resistance.

“One of the most exciting aspects of this work was that we had worked hard to design broadly acting inhibitors against many different resistant forms of the enzymes, and these designs proved very effective against two new enzymes we had never considered or previously studied,” said researcher Dennis Wright, PhD.

To create these drug candidates, the investigators targeted the bacteria’s use of folate (vitamin B9), which is known to be essential to MRSA. They hypothesized that if folate was inhibited, the bacteria would die, according to the study.

Currently, the only antibacterial antifolate drug marketed is trimethoprim, but MRSA has developed resistance to its mechanisms. To combat this resistance, the researchers analyzed the molecular structure of the enzyme, and how it interacted with molecules to complete its function.

By achieving an understanding of the mechanisms of the molecule, investigators were able to create novel formations of antifolates. Antifolates are created to bind with the molecule, so if the enzyme changes and evades them, it will not be able to do its job, which could make it more difficult for the bacteria to develop resistance, according to the study.

Thus far, the novel drugs’ success against trimethoprim-resistant MRSA shows promise. The researchers are continuing to collect various MRSA strains to further test their novel drugs.

“We’d like to determine if the resistance mechanisms we discovered in our local MRSA strains are also found in other clinics throughout the United States,” said Jeffrey Aeschlimann, PharmD, an associate of pharmacy practice at the University. “We also may find other novel resistance mechanisms. In both cases, we will be able to gain even more valuable information about our how our new antibiotics work against MRSA.”